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BACKGROUND: Substance use is common among individuals with psychotic disorders, but limited research exists on the variations in substance use across countries in Africa. This study aims to investigate the frequency of alcohol, tobacco, cannabis, and khat consumption in individuals with bipolar disorder (BD) and schizophrenia (SCZ) across four African countries: South Africa, Ethiopia, Kenya, and Uganda.METHODS: We utilized data from the Neuropsychiatric Genetics of African Populations-Psychosis project, a large case-control study which will soon have genetic data on over 42,000 participants, half with psychosis. Information on substance use was collected using the Alcohol, Smoking and Substance Involvement Screening Test v3 (ASSIST). The outcome was categorized into never (lifetime usage, no), irregular usage (weekly or monthly) and regular (daily use) based on reported frequency in the past three months. Each substance was modeled individually as an outcome in ordinal regression model adjusting for demographic factors of sex, education and country. Stratified analyses were performed to assess country-specific effects.RESULTS: Individuals with BD had significantly higher odds of alcohol consumption compared to those with SCZ. Males showed higher odds of alcohol, tobacco, and khat consumption compared to females. Significant variations in alcohol, tobacco, and cannabis consumption were observed across different study countries. Education level was significantly associated with khat consumption, with higher education levels associated with lower odds of consumption.CONCLUSION: Country and sex-specific differences in substance use behaviors exist in a large-scale African case-control study of people with psychosis. The findings here are in line with previous work regarding sex and regional differences, though they differ from studies conducted in US populations in that minimal evidence was found to support a relationship between level of education and frequency of substance use for any of the substances studied. This suggests that there may be distinct sociodemographic correlates of substance use in Africa and highlights the critical need to consider individuals of diverse ancestry in large-scale studies while also taking into account regional differences when examining substance use behaviors.